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J. Biol. Chem., Vol. 278, Issue 23, 20457-20460, June 6, 2003

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Rapamycin-induced Translational Derepression of GCN4 mRNA Involves a Novel Mechanism for Activation of the eIF2 Kinase GCN2^*

Hiroyuki Kubota  , Tohru Obata ¶, Kazuhisa Ota  || **, Takuma Sasaki ¶ || and Takashi Ito  ** 

From the Division of Genome Biology, ^¶Division of Experimental Therapeutics, and ^||Center for the Development of Molecular Target Drugs, Cancer Research Institute, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-0934, and the ^**Institute for Bioinformatics Research and Development (BIRD), Japan Science and Technology Corporation (JST), 5-3 Yonbancho, Chiyoda-ku, Tokyo 102-0081, Japan

When starved for amino acids, Saccharomyces cerevisiae accumulates uncharged tRNAs to activate its sole eukaryotic initiation factor (eIF) 2 kinase GCN2. Subsequent phosphorylation of eIF2 impedes general translation, but translationally derepresses the transcription factor GCN4, which induces expression of various biosynthetic genes to elicit general amino acid control response. By contrast, when supplied with enough nutrients, the yeast activates the target of rapamycin signaling pathway to stimulate translation initiation by facilitating the assembly of eIF4F. A cross-talk was suggested between the two pathways by rapamycin-induced translation of GCN4 mRNA. Here we show that rapamycin causes an increase in phosphorylated eIF2 to translationally derepress GCN4. This increment is not observed in the cells expressing mammalian non-GCN2 eIF2 kinases in place of GCN2. It is thus suggested that rapamycin does not inhibit dephosphorylation of eIF2 but rather activates the kinase GCN2. This activation seems to require an interaction between the kinase and uncharged tRNAs, because rapamycin, similar to amino acid starvation, fails to induce eIF2 phosphorylation in the cells with GCN2 defective in tRNA binding. However, in contrast with amino acid starvation, rapamycin activates GCN2 without increasing the amount of uncharged tRNAs, but presumably by modifying the tRNA binding affinity of GCN2.

Received for publication, March 27, 2003

^* This work was supported in part by grant-in-aid for Scientific Research on Priority Areas (C) "Genome Biology" from the Ministry of Education, Culture, Sports, Science and Technology of Japan and grant-in-aid for Scientific Research (B) from Japan Society for Promotion of Science (JSPS). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of postdoctoral fellowship from JSPS.

To whom correspondence should be addressed: Division of Genome Biology, Cancer Research Inst., Kanazawa University, 13-1 Takaramachi, Kanazawa 920-0934, Japan. Tel.: 81-76-265-2726; Fax: 81-76-234-4508; E-mail: titolab{at}kenroku.kanazawa-u.ac.jp.

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